JP2008239500A - Leptin secretion promoter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a leptin secretion promoter. <P>SOLUTION: The invention provides a leptin secretion promoter produced by using a krill extract as an active component, the above leptin secretion promoter wherein the extract is the dried granule of krill or non-heated krill, the leptin secretion promoter wherein the extract is an ethanol extract and an obesity preventing and/or treating agent containing the leptin secretion promoter. The above agents are useful as obesity preventing and/or treating agents, medicines or foods. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a leptin secretion promoter containing a krill extract as an active ingredient, and an obesity prevention and / or treatment agent containing the leptin secretion promoter.

  Obesity is the basis of metabolic syndrome that causes hypertension, diabetes, and hyperlipidemia, and greatly contributes to the onset and progression of arteriosclerotic diseases such as myocardial infarction and cerebrovascular disorder. Various factors are considered to be related to the establishment of obesity, and it is known that leptin (ob protein) plays an important role in it. Leptin is a hormone consisting of 146 amino acids, and exerts strong feeding suppression by acting on the hypothalamus (Non-patent Document 1), and at the same time acts on skeletal muscles to increase energy consumption (Non-patent document 1). Patent Document 2).

  The role of such leptin has been clarified because ob / ob mice having leptin dysfunction associated with gene mutation lead to high obesity due to overeating and a decrease in energy consumption (Non-patent Document 3). In addition, it has already been confirmed that leptin administration to ob / ob mice strongly suppresses body weight, body fat percentage, and food intake (Non-patent Documents 4 and 5). In addition, the therapeutic effect of leptin on type 2 diabetes, insulin secretion-reduced diabetes, and lipotrophic diabetes has also been reported (Non-patent Document 6).

  Leptin is mainly produced in fat cells and secreted into the blood. Therefore, if the amount of leptin in the blood can be increased or leptin secretion by adipocytes can be promoted, it is considered possible to prevent treatment of metabolic syndrome together with diet by suppressing overeating and increasing energy consumption. Based on this idea, for example, genetically modified leptin (Patent Documents 1 and 2), or a specific site in the leptin gene is replaced with another amino acid to suppress aggregation of the expressed protein and increase protein activity (Patent Document) 3) In addition, a substance containing malic acid, succinic acid, or the like as an active ingredient has been already reported as one that promotes secretion of leptin (Patent Document 4).

Y. Minokoshi et al., Nature, 2004, Vol. 428, p. 569-574 Y. Minokoshi et al., Nature, 2002, Vol. 415, p. 339-343 Y. ZHANG et al., Nature, 1994, Volume 372, p. 425-432 Perimounter et al., Science, 1995, Vol. 269, p. 540-543 J.L. Halaas et al., Science, 1995, Vol. 269, p. 543-546 Ken Ebihara, Kazukazu Nakao, “Clinical application of leptin in the field of diabetes”, Cell Engineering, Shujunsha, May 2005, Vol. 24, p. 476-480 Japanese National Patent Publication No. 9-506264 Japanese National Patent Publication No. 11-511165 JP-A-10-179158 JP 2001-187732 A

  If a substance capable of promoting leptin secretion is found, it becomes possible to treat or prevent diseases based on the pathogenesis of metabolic syndrome. Therefore, an object of the present invention is to provide a leptin secretion promoter, and a drug and food useful for treatment / prevention of various diseases based on the leptin secretion promoter.

  In light of the above-mentioned circumstances, the present inventors have sought extensively in nature for substances that promote leptin secretion, and as a result of intensive search, we have developed a krill extract, specifically a dried krill granule or an unheated ethanol extract. The present inventors have found a substance having a leptin secretion promoting action and have completed the present invention. Therefore, this invention relates to the leptin secretion promoter which uses a krill extract as an active ingredient. In addition, the present invention relates to the leptin secretion promoter, wherein the krill extract is a dried krill granule or a non-heated product. The present invention also relates to the leptin secretion promoter, wherein the extract is an ethanol extract. Furthermore, the present invention relates to an agent for preventing and / or treating obesity containing the leptin secretion promoter.

  The leptin secretion promoter of the present invention suppresses calorie intake and activates sugar and lipid metabolism by increasing the amount of leptin secretion from adipocytes. Therefore, obesity associated with excessive calorie intake and reduced calorie consumption can be suppressed, which is useful for prevention and treatment of metabolic syndrome such as hypertension, diabetes and hyperlipidemia.

The present invention relates to an agent for preventing and / or treating obesity comprising a krill extract as an active ingredient. The kind of krill that is a raw material of the krill extract used in the present invention is not particularly limited, but is particularly preferably a dry granule from which water is removed using Euphausia superba , or non-heated krill. Products, particularly preferably frozen products are used. According to the method described in JP-A-2000-139419, dried krill granules can be obtained by removing seawater from krill and crushing it, followed by heating and drying. good. In addition, frozen products are generally available as non-heated products of krill. This frozen product can be used as it is or after lyophilization. This may be crushed and used in the subsequent extraction process. The extract is not particularly limited as long as it is extracted with an organic solvent, but an extract extracted with ethanol is particularly preferable. The extract may be extracted according to a conventional method.For example, after freeze-drying the gonads, extract with 5 to 100 ml of ethanol per gram, remove the insoluble residue by centrifugation or the like, and concentrate the supernatant with an evaporator, etc. Inventive components can be obtained.

  The agent of the present invention has leptin secretion promoting activity and is useful as an agent for preventing and / or treating obesity. The agent of the present invention can be safely administered to humans and animals using the krill extract, which is the active ingredient of the present invention, as an active ingredient. When the agent of the present invention is used as a medicine, the compound that is the active ingredient of the present invention may be a pharmacologically acceptable salt. Salts with pharmacologically acceptable acids include inorganic acids with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, Examples include acid addition salts with organic acids such as lactic acid, malic acid, citric acid, and tartaric acid. Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, organic bases such as methylamine, ethylamine, and ethanolamine, or salts with basic amino acids such as lysine, arginine, ornithine, and ammonium. Salt. This compound or a pharmacologically acceptable salt thereof is safely administered orally or parenterally as a pharmaceutical to humans and animals. Examples of parenteral administration include administration methods such as intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, nasal administration, enteral administration, buccal administration, and transmucosal administration. Examples of the dosage form include injections, suppositories, aerosols, and transdermal absorption tapes. Oral preparations include, for example, tablets such as sugar-coated tablets, coated tablets, buccal tablets, capsules including powders, soft capsules, granules, pills, troches, or syrups including suspensions, emulsions, dry syrups, elixirs And liquid agents such as agents. Furthermore, these pharmacologically acceptable sustained release preparations and the like can be mentioned.

  These preparations are administered as a pharmaceutical composition together with a pharmacologically acceptable base, carrier, excipient, disintegrant, lubricant, colorant and the like according to known pharmaceutical manufacturing methods. Carriers and excipients used in these formulations include, for example, lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose and the like, and binders include, for example, starch, tragacanth gum, Gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, etc. Examples of disintegrants include starch, agar, gelatin powder, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, crystalline cellulose, calcium carbonate Examples of lubricants such as sodium bicarbonate and sodium alginate include magnesium stearate Talc, hydrogenated vegetable oil, macrogol, those which are allowed to added to pharmaceuticals as coloring agents, can be used respectively. Tablets and granules are sucrose, gelatin, hydroxypropylcellulose, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate as required The film may be coated with one or more layers using a methacrylic acid polymer or the like. Furthermore, capsules of substances such as ethyl cellulose and gelatin may be used. Moreover, when preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and each injection is prepared by a conventional method.

  When the agent of the present invention is administered to a patient as a medicament, it varies depending on conditions such as the degree of symptoms, the age, weight, and health status of the patient, and is not particularly limited, but for adults, 100 μg to 1000 mg / kg / day is administered orally or not. Orally once or more daily. When ingested as a food, it can be added to, mixed in, or applied to any food according to the dosage. Further, as a so-called health food, it can be made the same as the above-mentioned pharmaceutical preparation for oral administration.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not restrict | limited by these.

(1) Preparation of krill extract components
Production Example 1
200 liters of 92% ethanol was added to 20 kg of dry powder (SKP; manufactured by Nippon Suisan Co., Ltd.) of Antarctic krill ( Euphausia superba ), and the obtained soluble substance was concentrated under reduced pressure to obtain 21.6 kg of extract. Next, 1 liter of 99.5% ethanol was added to 100 g of this extract, and the obtained soluble substance was concentrated by a rotary evaporator to obtain an extract. This gave 42 g of final extract.

Production Example 2
400 liters of 92% ethanol was added to 80 kg of raw frozen product of Antarctic krill ( Euphausia superba ), and the resulting soluble material was concentrated under reduced pressure to obtain 12.9 kg of extract. Next, 1 liter of 99.5% ethanol was added to 100 g of this extract, and the obtained soluble substance was concentrated by a rotary evaporator to obtain an extract. This gave 10 g of final extract.

Measurement of Leptin Secretion Promoting Activity of the Present Invention Leptin secretion amount was examined using white adipose precursor cells (manufactured by Takara Bio Inc.) isolated from the rat peritoneum. 4 × 10 ³ white adipose precursor cells per well were added to a collagen-coated 96-well culture plate (Asahi Techno Glass Co., Ltd.), 10% newborn calf serum and 10 mM ascorbic acid, 1 μM octanoic acid, 10 nM triiodothylo Culture was performed in Dulbecco's modified Eagle's medium: Ham F-12 (1: 1) mixed medium containing nin. After culturing white adipose precursor cells for 2 days, differentiation was induced by further culturing in a medium further supplemented with 1 μM dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine, 10 ng / ml insulin. The cells were further treated with Dulbecco's modified Eagle's medium: Ham F-12 (1: 1) mixed medium containing 10% newborn calf serum and 10 mM ascorbic acid, 1 μM octanoic acid, 10 nM triiodothyronine, 10 ng / ml insulin for another 5 days. Cultured. When the medium is renewed, the krill dry powder (SKP; manufactured by Nihon Suisan Co., Ltd.), which is the active ingredient of the present invention, or the extract extracted from ethanol after crushing the krill frozen product (the ones in Production Examples 1 and 2) is added. On the fifth day, the culture supernatant was collected, and the secreted leptin concentration was measured with a rat leptin measurement kit (manufactured by Morinaga Bioscience Institute). In addition, the measurement was performed according to the description of the instruction manual attached to the kit.

  The extract of the present invention was redissolved in ethanol and added to the medium as described above. The final concentration when each extract was added was 100 μg / ml. The results are shown in FIG. FIG. 1 shows the results of measuring the concentration of leptin secreted in the culture supernatant after adding each extract from dried krill granules and frozen krill to the culture medium. Each extract promoted leptin secretion from white adipocytes more than twice. In addition, this promoting action is specific to leptin secretion and was not due to promotion of differentiation into adipocytes. Furthermore, leptin secretion increased depending on the concentration of the extract. From the above results, it was confirmed that krill has an effect of significantly promoting leptin secretion from white adipocytes. Therefore, it was confirmed that the active ingredient of the present invention has an excellent leptin secretion promoting effect.

  According to the present invention, a leptin secretion enhancer comprising a krill extract as an active ingredient, specifically, a leptin secretion enhancer comprising, as an active ingredient, a krill dry granule or an unheated ethanol extract, and the leptin secretion enhancer A prophylactic and / or therapeutic agent for obesity is provided. The agent of the present invention is useful as a pharmaceutical or food as an agent for preventing and / or treating obesity.

The leptin secretion promoting action of the active ingredient of the present invention in Example 2 is shown.

Claims (4)

A leptin secretion promoter containing krill extract as an active ingredient. The leptin secretion promoter according to claim 1, wherein the krill extract is a dried krill or non-heated product. The leptin secretion promoter according to claim 1 or 2, wherein the extract is an ethanol extract. An agent for preventing and / or treating obesity comprising the leptin secretion promoter according to any one of claims 1 to 3.

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